Endemic Burkitt's lymphoma (eBL) is the most common pediatric cancer in sub-Saharan Africa. Endemic BL is an aggressive B cell lymphoma with two infectious cofactors: early Epstein Barr virus (EBV) infection and frequent Plasmodium falciparum malaria. Recent research suggests that P. falciparum parasites increase the lytic activation of EBV from B cell lines. It was shown that P. falciparum parasites exert their effect o EBV through polyclonal activation B cells. Plasmodium falciparum parasites contain multiple polyclonal B cell activators, including CpG DNA, which stimulates toll-like receptor 9 (TLR9). It was recently shown that activation of B cells using CpG oligonucleotide sequences increased the infection and EBV-induced proliferation of B cells. It has not been shown, however, whether P. falciparum parasites increase the primary EBV infection and EBV-induced proliferation of B cells. Our preliminary in vitro and in vivo studies suggest that P. falciparum indeed increases these measures. We observed an increased frequency of EBV infected cells in children in a high malaria area compared to those in a nearby low malaria area of western Kenya by quantitative PCR. To further determine the interaction of P. falciparum and EBV in regard to eBL we have proposed the following studies. We will complete an in vitro study to determine the effects of P. falciparum on the establishment of EBV latency. We hypothesize that exposure to P. falciparum parasites will increase the EBV-induced proliferation, EBV load, or alter the EBV infected B cell phenotype of B cells in vitro. We will also translate our work to the clinic by performing an acute P. falciparum malaria field study in western Kenya to determine whether P. falciparum malaria activates B cells and increases their susceptibility to EBV infection in vivo. We will compare the B cell activation and EBV infection of individual B cells from P. falciparum malaria patients and healthy controls. This will allow us to make conclusions about which B cell type harbors the increased EBV we observed with our preliminary studies. Overall, this work will determine the interaction of P. falciparum and EBV with the goal of discovering preventative strategies for eBL. PUBLIC HEALTH RELEVANCE: Burkitt's lymphoma is the most common childhood cancer in sub-Saharan Africa. The development of Burkitt's lymphoma has been linked to Epstein Barr virus and malaria, but how these common infections lead to cancer is not understood. Understanding how Epstein Barr virus and malaria interact is critical for preventing Burkitt's lymphoma.